Gout is a chronic metabolic disease mainly characterized by hyperuricemia and pain caused by deposition of monosodium urate (MSU) at sites such as joints and the like, and is mainly due to purine metabolic disorders and/or uric acid excretion disorders. There are now tens of millions of patients suffering from gout in the world.
The current drugs for the treatment of hyperuricemia and gout mainly include: i) anti-inflammatory analgesic drugs for the control of joint swelling, pain and other symptoms when acute attack of gout occurs, such as colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs) and the like; ii) drugs for inhibiting the production of uric acid, such as xanthine oxidase (XO) inhibitors such as allopurinol, oxipurinol, febuxostat and the like; iii) drugs for the excretion of uric acid, such as probenecid, benzbromarone and the like; iv) uricolysis drugs for rapidly lowering blood uric acid when acute attack of gout occurs, such as uricase and pegylated uricase (pegloticase). However, these drugs all have significant side effects, for example, colchicine can cause diarrhea, vomiting, abdominal cramps and other common adverse effects, which is the first indication of its toxicity, with a therapeutically effective dose being close to the dose at which it causes gastrointestinal symptoms; probenecid can cause renal colic and renal dysfunction; benzbromarone has the risk of causing fulminant hepatitis; allopurinol has liver and bone marrow toxicity, allergic reactions and other adverse effects; uricase preparation is administered by injection, which leads to worse patient compliance than that of oral preparation, therefore it is only suitable for lowering blood uric acid when acute attack of gout occurs but not suitable for long-term treatment.
Urate transporter 1 (URAT1) located on the brush-like edge of renal proximal tubular epithelial cell is an important urate transporter in the kidney found in recent years, which is responsible for reabsorption of uric acid in kidney (Enomoto, A.; Kimura, H.; et al. Nature, 2002, vol 417, 447-452). Obviously, inhibition of URAT1 would inhibit the reabsorption of uric acid in kidney, increase excretion of uric acid in urine, and thereby achieve the object to lower blood uric acid and control attack of gout. Preclinical study and clinical study from Lesinurad et al. have demonstrated the curative effect of URAT1 inhibitors on the treatment of hyperuricemia and gout (Fleischmann, R.; Kerr, B.; et al. Rheumatology, 2014, vol 53, 2167-2174).
Lesinurad (RDEA 594) is an oral drug developed by Ardea Biosciences, Inc. that is capable of inhibiting URAT1 and excreting blood uric acid, and is initially developed from antiviral drug RDEA806 of Valeant Pharmaceuticals International, Inc. (as shown below). A new drug application for Lesinurad has now submitted to EMA (US2013345271 and WO2014008295), the benefits of which have already belonged to Astra Zeneca.

The present invention discloses a carboxylic acid URAT1 inhibitor containing a diarylmethane structure, which can be used in the preparation of medicaments for the treatment of hyperuricemia and gout.